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Abstract:

Formulations for oral transmucosal compositions including clomiphene-like
selective estrogen receptor modulators (C-SERMs) in combination with
transmucosal absorption enhancers are disclosed. Oral transmucosal
compositions can be for fast release or slow release, and can be
administered to induce ovulation in a female patient and thereby reduce
symptoms of anovulatory infertility, unexplained infertility, and the
like. Oral transmucosal compositions include liquid dosage forms, solid
dosage forms, and chewing gums. Further dosage forms include mucoadhesive
thin strips, thin films, tablets, patches, and tapes, among others. Other
dosage forms are: mucoadhesive liquids, such as, for example gel-forming
liquid; gel-forming semisolids; and gel-forming powders, among other
dosage forms that exhibit mucoadhesive properties, and provide oral
transmucosal delivery of C-SERMs. Oral transmucosal compositions will
deliver C-SERMs directly into the patient's bloodstream, and provide high
bioavailability of C-SERMs; therefore, the required doses are lower.

Claims:

1. A pharmaceutical composition for inducing ovulation comprising one or
more clomiphene-like selective estrogen receptor modulators (C-SERMs),
wherein the dosage form of the composition is oral transmucosal enabling
delivery of C-SERMs directly into a patient's bloodstream.

2. The pharmaceutical composition of claim 1, wherein the C-SERM is
clomiphene or analogs thereof.

3. The pharmaceutical composition of claim 2, wherein the clomiphene is
clomiphene citrate or an analog thereof.

4. The pharmaceutical composition of claim 1, wherein the C-SERM is
enclomiphene, zuclomiphene, or combinations thereof.

5. The pharmaceutical composition of claim 1, wherein clomiphene is
administered at about 5 mg/day to about 100 mg/day.

7. The pharmaceutical composition of claim 1, wherein the dosage form of
the composition is selected from the group consisting of: a solid, a
liquid, a semi-solid, a chewing gum, a gel-forming liquid, and
gel-forming powder.

8. The pharmaceutical composition of claim 7, wherein the solid dosage
form is a sublingual tablet or a buccal troche.

9. The pharmaceutical composition of claim 7, wherein the liquid dosage
form is selected from the group consisting of: sublingual solution,
emulsion, suspension, and liquid spray.

10. The pharmaceutical composition of claim 7, wherein the semi-solid
dosage form is selected from the group consisting of: gel, gel-forming
ointment, and gel-forming paste.

[0005] Infertility can be defined as the inability to achieve pregnancy in
a one-year period of regular unprotected sexual intercourse. Female
infertility can refer to the inability to conceive and/or to carry a
pregnancy to term. Despite the difficulties in estimating the prevalence
of infertility, it is generally accepted that one out of every four women
is infertile during one or more periods of time throughout the
reproductive portion of her lifetime.

[0006] The main causes of infertility among women include ovulatory
disorders, reproductive tract pathologies, reduced oocyte quality and
follicular depletion inherent to aging. Some forms of ovulatory disorders
include when ovulation does not occur because of the inability of the
hypothalamus to secrete gonadotropin-releasing hormone (GnRH), which
stimulates the pituitary gland to produce the luteinizing hormone (LH)
and follicle-stimulating hormone (FSH) that triggers ovulation. Ovulation
problems may also be due to polycystic ovary syndrome (PCOS), thyroid
gland disorders, adrenal gland disorders, excessive exercise, diabetes,
weight loss, obesity, or psychological stress. There are also a
considerable number of women with unexplained infertility, also called
idiopathic infertility. One of the possible causes of idiopathic
infertility could be related to deficiencies in the implantation process.

[0007] Conventional treatments for female infertility include the
administration of active pharmaceutical ingredients (APIs) for treating
infertility related to hormonal problems (e.g., ovulation disorders), in
vitro fertilization, and intrauterine insemination techniques. All these
treatments involve APIs being administered through various oral and
injectable delivery methods.

[0008] Clomiphene is a selective estrogen receptor modulator that has been
used for treating ovulation disorders. Selective Estrogen Receptor
Modulators (SERMs) are structurally unique compounds that interact with
intracellular estrogen receptors in target organs. SERMs can possess
either antagonist or agonist properties, and in certain cases, may
possess both properties. Some SERMs, such as tamoxifen and raloxifene
possess estrogen agonist properties that cause unusual pharmacological
effects to be exhibited when these particular SERMs interact with certain
tissues (e.g., bone, liver and cardiovascular system tissues).
Additionally, these same SERMs possess estrogen antagonist properties
when these particular SERMs interact with other tissues (e.g., brain and
breast tissues). Finally, these same SERMs possess mixed
agonist/antagonist properties when interacting with uterine tissue.
Clomiphene and SERMs that mimic clomiphene act specifically as an
estrogen antagonist in the brain, specifically in the hypothalamus and
pituitary sites.

[0009] Within the estrogen-negative feedback mechanism, estradiol slows
down the release of GnRH from the hypothalamus which in turn results in
the reduction of LH/FSH production by the pituitary gland. Clomiphene
acts to increase the production and release of GnRH by the hypothalamus
as well as production and release of LH and FSH from the pituitary gland.
LH and FSH then act on the ovaries to increase ovarian follicular
activity and eventual ovulation.

[0010] Oral dosage forms usually subject the API to degradation in the
gastrointestinal tract and the first pass metabolism in the liver, and
are commonly associated with a delayed onset of the effects of the
treatment. Injections and implanted pellets can cause local pain to the
recipient as well as require the assistance of health care professionals
thereby making these dosage delivery forms inconvenient and expensive.

[0011] Transdermal administration (e.g., implanted pellets, patches, gels,
etc.) possesses the benefits of the avoidance of the first-pass
metabolism as well as degradation in the gastrointestinal tract.
Transdermal administration typically includes the added benefit that the
treatment is not painful. Unfortunately, transdermal compositions,
excluding implant pellets, are often associated with low percentages of
absorption through the skin. Another drawback is that a large part of the
API remains on the skin with the potential risk of being transferred to
another person through direct skin-to-skin contact. Additionally, the
non-absorbed portion of the APIs is lost to the surrounding environment
making these formulations non-environmentally-friendly.

[0012] Oral transmucosal delivery is a particularly advantageous delivery
route because it is a non-invasive drug delivery method. Oral
transmucosal delivery promotes better patient compliance and involves
lower costs than invasive procedures, such as, injection and implantation
of pellets. Oral transmucosal delivery also results in a much shorter
onset time (e.g., the time from administration to therapeutic effect)
than oral delivery and may be easily self-administered. Oral transmucosal
administration involves the patient holding the composition within the
oral cavity (e.g., between the cheek and gum, beneath the tongue, etc.)
while the API dissolves in the available fluid (e.g., saliva), diffuses
through the mucosa lining of the mouth, and enters the bloodstream
bypassing the gastrointestinal tract as well as hepatic metabolism.

SUMMARY

[0013] The present disclosure refers to oral transmucosal compositions
that include one or more clomiphene-like selective estrogen receptor
modulators (C-SERMs) as APIs in combination with transmucosal absorption
enhancers to induce ovulation in a female patient and reduce symptoms of
anovulatory infertility, unexplained infertility, and the like. In some
embodiments, APIs include C-SERMs, such as, clomiphene (Clomid®),
analogs thereof, or any other chemical compound that acts on estrogen
receptors to block the normal estrogen feedback control of the
hypothalamus and subsequent negative feedback control on the pituitary
gland.

[0014] In some embodiments, the C-SERM employed in oral transmucosal
compositions is clomiphene. In these embodiments, clomiphene within oral
transmucosal compositions is implemented as clomiphene citrate or an
analog thereof. In other embodiments, clomiphene implemented within oral
transmucosal compositions is zuclomiphene, enclomiphene, or a combination
of these two clomiphene isomers.

[0016] In some embodiments, the amount of absorption enhancers included in
oral transmucosal compositions range from about 0.1% to about 20%; with
the most suitable amount being about 1% to about 10%. These percent
ranges may refer to % weight by weight, % weight by volume, or % volume
by volume.

[0017] In some embodiments, oral transmucosal compositions allow the
delivery of C-SERMs directly into the patient's bloodstream bypassing the
gastrointestinal tract and the hepatic metabolism. Bypassing the hepatic
metabolism results in a higher percentage of bioavailability of C-SERMs
to the patient.

[0020] In some embodiments, oral transmucosal dosage forms include
mucoadhesive polymers as part of the compositions. Examples of dosage
forms having mucoadhesive polymers include mucoadhesive thin strips, thin
films, tablets, patches, and tapes, among others. In other embodiments,
dosage forms include: mucoadhesive liquids, such as, gel-forming liquids;
semisolids, such as, for example gels, gel-forming ointments, and
gel-forming pastes; gel-forming powders; or any other dosage forms that
exhibit mucoadhesive properties and provide oral transmucosal delivery of
C-SERMs.

[0021] In some embodiments, oral transmucosal compositions are
administered in the oral cavity at the sublingual, palatal, buccal,
gingival, or the like.

[0022] In some embodiments, oral transmucosal compositions can be tailored
for individual patients according to clinical symptoms and baseline serum
concentrations of estradiol, LH, and/or progesterone. These oral
transmucosal compositions can be prescribed with various concentrations
of C-SERMs, and suitable dosage regimens to more closely mimic the
circadian rhythm and physiological pulsatile secretion of GnRH, thereby
keeping the LH/FSH and estradiol levels within physiologic ranges
suitable for inducing conception.

[0023] In some embodiments, oral transmucosal compositions are
administered within a dosage range from about 5 mg/day to about 100
mg/day of clomiphene, preferably from about 25 mg/day to about 50 mg/day.
In these embodiments, oral transmucosal compositions are administered for
about 5 days and starting at or around days 2-5 of the menstrual cycle,
at the convenience of the amenorrheic or oligomenorrheic patient, or at
the recommendation of the treating physician.

[0024] In some embodiments, oral transmucosal dosage forms are designed
for fast release and transmucosal absorption of C-SERMs. In other
embodiments, oral transmucosal dosage forms are designed for slow release
and absorption of C-SERMs over a prolonged period of time.

[0025] In some embodiments, a low dose C-SERM in any of the above
identified dosage forms can result in acceptable ovulation inducting
levels in the patient.

[0026] Numerous other aspects, features, and benefits of the present
disclosure may be made apparent from the following detailed description.

DETAILED DESCRIPTION

[0027] The present disclosure is described here in detail. Other
embodiments may be used and/or other changes may be made without
departing from the spirit or scope of the present disclosure. The
described embodiments are not meant to limit the subject matter presented
here.

DEFINITIONS

[0028] As used here, the following terms have the following definitions:

[0029] "Absorption Enhancer" or, equivalently, "Penetration Enhancer"
refers to a substance used to increase the rate of permeation through the
mucous membrane, skin or other body tissue of one or more substances
(e.g., APIs) in a formulation.

[0030] "Active Pharmaceutical Ingredients (APIs)" refer to chemical
compounds that induce a desired effect, and include agents that are
therapeutically or prophylactically effective.

[0031] "Anovulatory Infertility" refers to a condition in which there is
no rupture of the follicle with subsequent release of an ovum.

[0034] "Treating" and "Treatment" refers to reduction in severity and/or
frequency of symptoms, elimination of symptoms and/or underlying cause,
prevention of the occurrence of symptoms and/or their underlying cause,
and improvement or remediation of damage.

[0035] "Vehicle" refers to a substance of no therapeutic value that is
used to convey at least one API for administration.

DESCRIPTION OF THE DISCLOSURE

[0036] Embodiments of the present disclosure are directed towards oral
transmucosal delivery of active pharmaceutical ingredient (APIs). Oral
transmucosal compositions that include clomiphene-like selective estrogen
receptor modulators (C-SERMs) as APIs in combination with transmucosal
absorption enhancers are disclosed. These oral transmucosal compositions
are proposed to induce ovulation in a female patient and reduce symptoms
of anovulatory infertility, unexplained infertility, and the like.

[0037] As described previously, estradiol serves as a major mediator of
sex steroid-gonadotropin feedback. Thus, the secretion of luteinizing
hormone (LH) and follicle-stimulating hormone (FSH) are, to a large
extent, modified by C-SERMs that affect the activity of estradiol.
C-SERMs possess the capacity to blunt the activity of estradiol by
competing with estradiol for the estrogen receptors of the hypothalamus
and pituitary gland thereby increasing the amount of LH and FSH the body
produces. These increased levels of LH and FSH correspond with increased
ovarian follicular activity and eventual ovulation. Therefore, C-SERMs
can be used for anovulatory infertility (e.g., anovulation and
oligoovulation), unexplained infertility, and the like.

[0038] Formulation

[0039] In some embodiments, oral transmucosal compositions include one or
more C-SERMs as APIs, transmucosal absorption enhancers, vehicles, and
additives, among other suitable ingredients. In these embodiments, APIs
include C-SERMs, such as, clomiphene (Clomid®), analogs thereof, or
any other chemical compound that acts on estrogen receptors to block the
normal estrogen feedback control of the hypothalamus and subsequent
negative feedback control on the pituitary gland.

[0040] In some embodiments, the C-SERM employed in oral transmucosal
compositions is clomiphene. In these embodiments, clomiphene within oral
transmucosal compositions is implemented as clomiphene citrate or an
analog thereof. In other embodiments, clomiphene implemented within oral
transmucosal compositions is zuclomiphene, enclomiphene, or a combination
of these two clomiphene isomers. The list of C-SERMs above is not
exhaustive; other compounds described in the art that meet the set
requirements can also be considered.

[0049] Effervescent agents are usually a combination of one or more acids
with one or more bases. Acids are selected from citric acid, tartaric
acid, and the like. Bases can be sodium bicarbonate or other suitable
agents that may react with acids, and produce gas.

[0050] In some embodiments, a stabilizing agent is used to stabilize the
API for a specific dosage form. In these embodiments, the stabilizing
agent used will depend on the API used as well as the other additive
ingredients. Any suitable chemical substance may be used as a stabilizing
agent. Stabilizing agents are known to those skilled in the art and
therefore will not be discussed further herein.

[0056] In some embodiments, the amount of absorption enhancers included in
oral transmucosal compositions range from about 0.1% to about 20%; with
the most suitable amount being about 1% to about 10%. These percent
ranges may refer to % weight by weight, % weight by volume, or % volume
by volume.

[0060] In some embodiments, oral transmucosal compositions allow the
delivery of C-SERMs directly into the patient's bloodstream bypassing the
gastrointestinal tract and the hepatic metabolism. Bypassing the hepatic
metabolism results in a higher percentage of bioavailability of C-SERMs
to the patient.

[0061] In some embodiments, oral transmucosal compositions are
administered in the oral cavity at the sublingual, palatal, buccal,
gingival, or the like. Oral transmucosal compositions may be
self-administered by the patient or administered by a medical
practitioner, such as a physician or nurse.

[0063] In some embodiments, oral transmucosal dosage forms include
mucoadhesive polymers as part of the compositions. Examples of dosage
forms having mucoadhesive polymers include mucoadhesive thin strips, thin
films, tablets, patches, and tapes, among others. In other embodiments,
dosage forms include: mucoadhesive liquids, such as, gel-forming liquids;
semisolids, such as, for example gels, gel-forming ointments, and
gel-forming pastes; gel-forming powders; or any other dosage forms that
exhibit mucoadhesive properties and provide oral transmucosal delivery of
C-SERMs.

[0064] In some embodiments, oral transmucosal dosage forms are designed
for fast release and transmucosal absorption of C-SERMs. In other
embodiments, oral transmucosal dosage forms are designed for slow release
and absorption of C-SERMs over a prolonged period of time.

[0065] In some embodiments, oral transmucosal compositions are
administered in a single administration whereby a certain amount of
C-SERM is administered together. In an example, one puff of a spray
solution is administered representing the full desired dose. In other
embodiments, oral transmucosal compositions are administered by multiple
administrations in one or more sub-doses over a specified period of time.
In an example, one, two or more puffs of a smaller dose of the oral
transmucosal composition are administered--preferably one after another
in quick succession.

[0066] In some embodiments, oral transmucosal compositions can be tailored
for individual patients according to clinical symptoms and baseline serum
concentrations of estradiol, LH, and/or progesterone. These oral
transmucosal compositions can be prescribed with various concentrations
of C-SERMs, and suitable dosage regimens to more closely mimic the
circadian rhythm and physiological pulsatile secretion of GnRH, thereby
keeping the LH/FSH and estradiol levels within physiologic ranges
suitable for inducing conception.

[0067] In some embodiments, the dosages (e.g., daily) required depend on
the type of C-SERM included in the disclosed oral transmucosal
compositions. In other words, some C-SERMs are more potent than others,
and hence, the dosage regimen varies among the various C-SERMs used. In
these embodiments, a low dose C-SERM in any of the above identified
dosage forms can result in acceptable ovulation inducting levels in the
patient.

[0068] In some embodiments, oral transmucosal compositions are
administered within a dosage range from about 5 mg/day to about 100
mg/day of clomiphene, preferably from about 25 mg/day to about 50 mg/day.
In these embodiments, oral transmucosal compositions are administered for
about 5 days and starting at or around days 2-5 of the menstrual cycle,
at the convenience of the amenorrheic or oligomenorrheic patient, or at
the recommendation of the treating physician.

[0069] The following examples are intended to illustrate the scope of the
disclosure and are not intended to be limiting. It is to be understood
that other pharmaceutical formulations known to those skilled in the art
may alternatively be used.

Examples

[0070] Exemplary dosage forms of the oral transmucosal compositions are
described below.

[0074] While various aspects and embodiments have been disclosed, other
aspects and embodiments are contemplated. The various aspects and
embodiments disclosed are for purposes of illustration and are not
intended to be limiting, with the true scope and spirit being indicated
by the following claims.